Osteoporosis is a major health concern linked to age-related decreases in circulating sex steroids that primarily affects bone mass and architecture in cancellous regions of the skeleton. Hormone therapy and exercise can be effective in counteracting this bone loss. One pathway by which these therapeutic factors may act is estrogen receptor-alpha (ER-alpha). However, the mechanisms by which estrogen, ER-alpha and mechanical loading maintain cancellous bone mass or stimulate bone growth are not well understood. The hypotheses to be evaluated in the proposed research are that (1) the structural and material response of the mouse tibial metaphysis to load will be greatest in peripubescent mice and will decrease with age to adulthood, mirroring ER-alpha expression in the bone;and (2) as ER-alpha is expected to be the primary effector of the adaptive response to load in the skeleton, this response will be significantly diminished in ER-alpha knockout mice relative to the wild types at each corresponding age. Specific Aims: To determine the corticocancellous response of the proximal metaphysis of the mouse tibia to loading with age in both wild type and ER-alpha knockout mice. These aims will be accomplished by applying compressive loads to the tibiae of three age groups of female wild type and ER-alpha knockout mice using an external loading device. The bone's response to the loading regimen in relation to age and ER-alpha expression will be addressed by examining the corticocancellous architecture, material properties, cellular activities, and load bearing capacity in the metaphysis relative to the unloaded limb. Significance: This project will produce unique data regarding the role of ER-alpha in normal bone development and load mechanotransduction. This work will demonstrate the efficacy of in vivo loading to maintain or stimulate growth in cancellous bone with age and the role of ER-alpha in normal bone development and in mediating bone's response to external loads. The goal of the proposed study is to understanding the molecular and mechanical mechanisms by which cancellous bone adapts to load, both in the presence and absence of estrogen. The insights gained by the proposed study are critical for developing therapeutic strategies to inhibit age-related and postmenopausal bone loss.